Clinical efficacy and applicability of natural products in the treatment and prevention of radiotherapy-induced oral mucositis: A systematic review

The aim of this systematic review was to describe the efficacy and acceptability of natural products in the management of oral mucositis caused by radiation. From the day it started to August 7, 2023, a thorough search for randomized controlled trials (RCTs) was carried out among seven databases: the Web of Science, PubMed, Embase, OVID, Scopus, the Cochrane Library and the CINAHL database. Only English-language articles were identified during the search. Using the revised Cochrane risk-of-bias tool, version 2, two researchers screened the articles, collected information on study characteristics, and appraised risks of bias. The data were analyzed and descriptively presented with a narrative synthesis methodology involving the Synthesis Without Meta-Analysis (SWiM) reporting element applied in detail. The PROSPERO registration number of this study is CRD42023476932. Thirty-six clinical trials were included in the study; the included studies included a variety of 20 types of natural products. Honey and Curcuma longa were the most commonly assessed natural products. A total of 2,400 participants reported taking part in therapy with natural products for oral mucositis. Natural products demonstrated substantial efficacy in terms of influencing intensity, incidence, pain score, quality of life, and symptoms such as xerostomia and dysphagia. Except for manuka honey, most natural products were well accepted. Regarding the clinical trials’ risk of bias, 2 clinical trials (5.56%) had a high risk of bias, 17 studies (47.2%) had a low risk of bias, and 17 studies (47.2%) were rated with “some concern.” Natural remedies work well as alternate treatments for managing oral mucositis caused by radiation therapy. However, additional clinical trials are still needed. The safety of these conventional medications as well as their effectiveness and safety when used in combination with other conventional or naturopathic therapies should be fully examined.


Introduction
The probability of developing mucositis is highly dependent on the sites irradiated.Patients who undergo routine radiotherapy (RT) fractionation for head and neck cancer have a greater

Eligibility criteria
The inclusion criteria were as follows: (a) population-adults with a diagnosis of oral mucositis after radiotherapy or combination of radiotherapy and chemotherapy; (b) interventionpatients in treatment groups received a single natural product or the natural product in combination with another therapeutic strategy; and (c) control-patients in control groups received placebo, other standard agents, nothing or a combination of the above; interventions could be administered by any route, formulation or dose; (d) outcome-the primary outcome was the severity of oral mucositis (including, e.g., the incidence, score, even time of onset, duration), and acceptability of medicines; the secondary outcome was access to other symptom complications (e.g., pain level, quality of life assessment and others; e.g., xerostomia, dysphagia and cytokines).
The exclusion criteria were as follows: duplicates, no access to the full text, literature reviews, trial protocols, clinical studies without a control group, research conducted in vitro or animal, studies using a drug solution containing ethanol, and studies that could not verify the composition of specific constituents.

Study selection and data extraction
Two authors eliminated irrelevant articles by reviewing the full title and abstract of each study based on the inclusion criteria.The eligibility of the articles was assessed by scanning the full texts of the articles that met the inclusion criteria, and detailed information on the study characteristics was independently extracted to data extraction forms.The extracted information was collected, including details about the author, study year, study design, participants, natural product of interventions, agent of comparators, agent administration route and outcome results.Disagreements were resolved by consensus or by consulting another researcher.

Evaluation of the risk of bias
Two reviewers separately evaluated the risk of bias.Randomized controlled trials were assessed using the revised Cochrane Risk-of-bias Tool for Randomized Studies (RoB 2) [14].Bias risk was divided into three categories: low, some concerns, and high.

Methods for synthesis
Given the variation in interventions across study designs and lack of standardized data about the Consolidated Standards of Reporting Trials (CONSORT) statement on standards for herbal and Chinese medicine interventions, it was not feasible to perform a meta-analysis.The synthesis of findings was directed by narrative synthesis methods and the Synthesis Without Meta-Analysis (SWiM) reporting guidelines [15].Synthesis descriptions were grouped according to outcome indicators.

Study characteristics
Fig 1 shows the process of database searching.A total of 817 studies were found.After completing the elimination of duplicate studies and assessing the titles and abstracts, we chose 69 studies for full-text evaluation.Finally, 36 studies that met the inclusion criteria were included in the qualitative analysis.Table 1 generalizes the features of the studies included in this review, including information on study location, study design, funding, intervention duration and participant sample size.The included studies spanned 21 years (2003 [16] to 2023 [17,18]).Table 2 shows the fundamental characteristics of the clinical trials using natural agents.Table 3 shows the main results of the primary and secondary outcomes of clinical trials included in the systematic review.

Quality of life assessment
A total of seven trials assessed patients' quality of life, mainly using the UW-QOL, EORTC QLC-C30 and EORTC QLC-H&N35 scales.Two [28,31] of the trials of aloe vera and manuka honey showed no significant results in terms of pain reduction, while the other six [18,24,29,34,45,46] trials of aloe vera, honey, black mulberry molasses, FITOPROT and SAMITAL1 showed a significant reduction in pain symptoms.

Acceptability
Twenty-five trials reported acceptability.In the studies by Su [31], Soni [22], Fasanaro [45] et al., good compliance was reported for patients treated with aloe vera, curcumin, and SAMI-TAL1.In the studies by Elyasi [35], Soltani [42] et al., patients showed good tolerance to silymarin and Plantago major L. In a study of Manuka honey, some subjects withdrew from the study due to the strong taste and moderate to severe nausea [28].

Adverse events
Among the trials that reported adverse events, nausea and vomiting were reported in the trials of aloe vera and Manuka honey [28,[30][31][32], and nausea, burning sensation in the mouth and gastrointestinal reactions were reported in the trials of SAMITAL1, silymarin, Plantago major L. and Shuanghuabaihe tablets [35,36,42,45,46,48].For Plantago major L., the adverse effects reported were gastrointestinal reactions and burning sensations in the mouth [42].The gastrointestinal reactions were mainly diarrhea with mild abdominal pain and cramps.Importantly, it is difficult to distinguish whether these side effects are caused by natural medicines or cancer radiotherapy, and it is necessary to report side effects consistently in each trial so that researchers can accurately assess treatment-related toxicity to minimize bias.

Risk of bias
The methodological quality of the 36 included studies is illustrated in Fig 2 and assessment of the risk of bias in each trial is showed in Fig 3 .The revised risk-of-bias tool ROB 2 was used to evaluate the risk of bias in each included trial.In domain 5, every study received a rating of "some concern."It is unknown whether articles of clinical trials or even records were analyzed in accordance with a predetermined plan that was finished before information on nonhidden outcomes was available for examination.

Discussion
The present study investigated the role of natural products in radiotherapy-induced oral mucositis.Natural products can simultaneously target different primary pathways that support pathobiology and affect the pathogenesis of mucositis at different levels without compromising the efficacy of antitumor regimens [53,54].In this respect, natural products are very good alternative therapies compared to synthetic drugs.
In this article, we categorized and reported the results of the effects of natural products on relieving oral mucositis, reducing pain, improving quality of life and ameliorating comorbidities such as xerostomia and dysphagia.Studies have shown that turmeric, honey, Zataria, Indigowood root, black mulberry molasses, SAMITAL1, Kangfuxin solution, and the Chinese herbal compounds Shuanghuabaije tablets, CHIN, and Qingreliyan decoction have favorable ameliorative therapeutic effects on radiotherapy-induced oral mucositis.However, most studies' outcomes were frequently constrained by the small number of participants involved and/ or lack of standardized intervention methodology.Even comparisons between the same drugs are difficult because of the limitations of the different concentrations used, dosages used, and extraction methods, such as essential oils (from manuka and kanuka), propolis, aloe vera, bluebell root and silymarin.The essential oils appeared to be effective in preventing OM due to their wound-healing, anti-inflammatory, antimitotic, analgesic, and antibacterial qualities, but an important limitation of the study was the small sample size [37].Although the use of very small doses of Manuka and Kanuka in a gargle may have a favorable effect on the development of radiation-induced mucositis, additional trials are needed to corroborate these findings, according to the findings of feasibility studies.Propolis is rich in flavonoids, which have healing, antiulcer, anti-inflammatory and antioxidant effects, and the findings of this study support this hypothesis regarding the management of oral mucositis; however, the small sample size was also the primary drawback of this study, and further research is needed to clarify the potential radioprotective mechanisms involved [38,55,56].Aloe vera has been shown to have anti-inflammatory, antimicrobial, antioxidant, antitumor, skin-protective and wound-healing pharmacological effects in several in vitro studies [57]; however, of the two studies included in this review, the study by Su et al. revealed no discernible impact of oral aloe vera solution in the treatment of mucositis [31].A study by Sahebjamee et al. revealed that aloe vera delayed the onset of mucositis and severe mucositis [30].There is still a need for extensive mechanistic studies on aloe vera extracts and further determination of the therapeutic effect of aloe vera by increasing the sample size, subdividing the type of primary site and conducting clinical trials with different routes of administration.Indigowood root has anti-inflammatory properties, and the component it contains, Indigofera, is thought to lessen the degree of dysphagia, anorexia, and oral mucositis caused by radiation therapy; however, the specific mechanism and pathway by which Indigowood root reduces radiotherapy-induced mucositis requires further analysis [41].Silymarin is extracted from Milk thistle (Silybum marianum L.).The extract contains several flavonolignans, the major component being silymarin, which is associated with many pharmacological properties, including antioxidant, anti-inflammatory, immunomodulatory and hepatoprotective properties [58,59].The efficacy of these agents in preventing radiotherapy-induced mucositis was increased in the included studies, but clinical trials with larger sample sizes, especially with different doses, durations and nanoformulations of silymarin, are advised to verify this possible effect [35].
This study has certain limitations, and there is room for methodological improvement in RCTs investigating natural products.First, because not all protocols or registration information from the included trials were available, the articles may have publication bias due to unpublished unfavorable or negative results.Some of the trials did not describe how allocation was concealed, and the presence of some drugs, such as honey, which could not be blinded, made the literature less reliable.Second, the WHO, RTOG, OMAS, NCI-CTCAE and OAG oral mucositis grading scales were used, the grading criteria were not standardized, and only a few trials reported that grading was performed by a person with a professional background in mucositis, making it difficult to compare the staging and grading of the disease.In addition, safety was described in general terms and not specifically documented using the relevant scales.Only one of the trials included in the review described the effect of therapy in combination with other conventional therapies for the treatment of radiation-related oral mucositis, and safety studies of natural products combined with other conventional and/or naturopathic therapies are incomplete.The safety and efficacy of these treatments need to be investigated further.
In conclusion, according to our review of trials, the application of natural remedies in the treatment of radiotherapy-induced oral mucositis exhibited good efficacy and safety.The vast majority of these natural products were well accepted, but in the manuka honey trial, patients withdrew from the study due to nausea and unpleasant taste.Nonetheless, there is a need to extend investigations by increasing the sample size, improving the dosing regimen, and assessing compliance with the CONSORT guidelines for the herbs and Chinese herbal medicines included, thereby enhancing the quality of the clinical trials.

Conclusion
The results of the present systematic review reveal that curcumin, honey, zataria, Indigowood root, black mulberry molasses, aloe vera, silymarin, Kangfuxin solution and the herb compounds Mucotrol™ FITOPROT, SAMITAL1, Shuanghuabaihe tablets, Qingreliyan decoction, and CHIN have favorable effects on the treatment of radiotherapy-induced oral mucositis.Additionally, we support the use of natural products to treat radiotherapy-induced oral mucositis.However, there is still a need for additional studies focusing on the safety of these traditional medicines and their efficacy and safety when used in combination with other conventional and/or naturopathic therapies.